Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran co-administered with different classes of antibiotics in healthy volunteers

Dorani, Hassan; Schützer, Kajs-Marie; Sarich, Troy C.; Wall, Ulrika; Logren, Ulrika; Ohlsson, Lis; Eriksson, Ulf G.

doi:10.1007/s00228-007-0292-6

Cited by 15 publications

(7 citation statements)

References 30 publications

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“…Co-administration of CIP with ximelagatran, an oral direct thrombin inhibitor that is a substrate for P-gp and is not metabolized by the CYP450 enzyme system, resulted in unchanged ximelagatran PK parameters [320]. …”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

et al. 2011

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Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug interactions of the commonly prescribed antimicrobial drugs oxazolidinones, rifamycines, macrolides, fluoroquinolones, and beta-lactams, focusing on systematic research. We describe drug-food and drug-drug interaction studies in humans, affecting antimicrobial drugs as well as concomitantly administered drugs. Since knowledge about mechanisms is of paramount importance for adequate management of drug interactions, the most plausible underlying mechanism of the drug interaction is provided when available. This overview can be used in daily practice to support the management of pharmacokinetic drug interactions of antimicrobial drugs.

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Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

et al. 2011

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“…This interaction is of no clinical relevance in patients receiving CFX instead of MFX (352). In addition, despite CFX induced Pglycoprotein inhibition, no alteration in ximelagatran pharmacokinetics were observed (353).…”

Section: P-glycoproteinmentioning

confidence: 85%

Fluoroquinolones, the Cornerstone of Treatment of Drug-Resistant Tuberculosis: A Pharmacokinetic and Pharmacodynamic Approach

Pranger¹,

Alffenaar²,

Aarnoutse

2011

CPD

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Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-administered agents on these characteristics, for the currently used FQs (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin) in TB treatment. Future FQs that are being developed may overcome the problems with FQs that are used in daily practice. Therefore PK and pharmacodynamic (PD) properties of novel FQs (clinafloxacin, garenoxacin, lomefloxacin, sitafloxacin, sparfloxacin, trovafloxacin, gemifloxacin, grepafloxacin and DC-159a) were evaluated in TB treatment as well. Integrating both excellent PK and PD properties, moxifloxacin, possibly at a higher dosage, may fulfil a far more important role in the treatment of multi-drug and early-generation FQ resistant TB than proposed in the current WHO guideline. Sparfloxacin, trovafloxacin and sitafloxacin are upcoming novel FQs that may be useful for drug-resistant TB based on their favourable PK properties or microbiological susceptibility against M. tuberculosis. Finally, the 8-methoxy moiety, as present in the chemical structure of MFX, will possibly provide DC- 159a with promising PK/PD characteristics and consequently this FQ may develop into a key FQ in future drug resistant TB treatment.

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“…38 These in vitro results have been confirmed in several clinical interaction studies, where known ABCB1 inhibitors such as azithromycin, clarithromycin, and amiodarone are reported to increase the plasma exposure of melagatran upon coadministration with ximelagatran (AstraZeneca, data on file). 39,40 In conclusion, we show that ximelagatran and melagatran were the predominant compounds excreted in bile after intraintestinal ximelagatran administration. Four minor hydroxylated metabolites of ximelagatran (<0.1% of dose) were detected, suggesting, for the first time, that ximelagatran may be metabolized by cytochrome P450 isoenzymes.…”

Section: Study 2: Effect Of Erythromycin On the Pharmacokinetics Of Xmentioning

confidence: 61%

“…This was further supported by the fact that knockdown of ABCB1 expression in Caco‐2 cells using shRNA resulted in reduced efflux ratios of ximelagatran, OH‐melagatran, and melagatran 38 . These in vitro results have been confirmed in several clinical interaction studies, where known ABCB1 inhibitors such as azithromycin, clarithromycin, and amiodarone are reported to increase the plasma exposure of melagatran upon coadministration with ximelagatran (AstraZeneca, data on file) 39 , 40 …”

Section: Discussionmentioning

confidence: 78%

Biliary Excretion of Ximelagatran and Its Metabolites and the Influence of Erythromycin Following Intraintestinal Administration to Healthy Volunteers

Matsson¹,

Eriksson²,

Knutson³

et al. 2011

The Journal of Clinical Pharmacology

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The biliary excretion of the oral thrombin inhibitor ximelagatran and its metabolites was investigated by using duodenal aspiration in healthy volunteers following intraintestinal dosing. In the first investigation, radiolabeled [(14)C]ximelagatran was administered, enabling quantification of the biliary excretion and identification of metabolites in the bile. In the second study, the effect of erythromycin on the biliary clearance of ximelagatran and its metabolites was investigated to clarify the reported ximelagatran-erythromycin interaction. Approximately 4% of the intraintestinal dose was excreted into bile with ximelagatran and its active form, melagatran, being the most abundant compounds. Four novel ximelagatran metabolites were identified in bile (<0.1% of dose). Erythromycin changed the pharmacokinetics of ximelagatran and its metabolites, with an elevated ximelagatran (78% increase), OH-melagatran (89% increase), and melagatran (86% increase) plasma exposure and higher peak plasma concentrations of the compounds being measured. In parallel, the biliary clearance was moderately reduced. The results suggest that inhibition of hepatobiliary transport is a likely mechanism for the interaction between erythromycin and ximelagatran. Furthermore, the study demonstrated the value of direct bile sampling in humans for the identification of primary biliary metabolites.

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Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran co-administered with different classes of antibiotics in healthy volunteers

Cited by 15 publications

References 30 publications

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

Fluoroquinolones, the Cornerstone of Treatment of Drug-Resistant Tuberculosis: A Pharmacokinetic and Pharmacodynamic Approach

Biliary Excretion of Ximelagatran and Its Metabolites and the Influence of Erythromycin Following Intraintestinal Administration to Healthy Volunteers

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